Process for the preparation of a tablet or dragee composition containing a heat-, light- and moisture-sensitive active ingredient having monoclinic crystal structure

ABSTRACT

The invention relates to a process for the preparation of a tablet or dragee composition containing a moisture-, heat- and light-sensitive compounds having monoclinic crystalline structure as active ingredients, which comprises homogenizing the active ingredient with 0.2 to 1.5 parts by weight of an anhydrous alkaline earth metal salt and 0.5 to 2.5 parts by weight of microcrystalline cellulose calculated for the active ingredient and optionally with one or more pharmaceutically acceptable carrier(s) and/or additive(s) and compressing the homogeneous mixture obtained to tablets in a manner known per se and, if desired, coating the tablet thus obtained in a manner known per se.

The invention relates to a process for the preparation of a tablet ordragee composition containing a heat-, light- and moisture-sensitiveactive ingredient having monoclinic crystal structure.

The process according to the invention is particularly useful forpreparing a pharmaceutical composition having antiarrhythmic activityand containing as active ingredient an aminoguanidine derivative of thegeneral formula (I), ##STR1## wherein R¹, R² and R³ stand independentlyfrom each other, for hydrogen, halogen or C₁₋₄ alkyl, nitro, C₁₋₄ alkoxyor trifluormethyl group;

R⁴ and R⁵ represent independently from each other, a C₁₋₄ alkyl group;

R⁶ and R⁷ represent, independently from each other, hydrogen or C₁₋₄alkyl or C₂₋₄ alkenyl group

or their acid addition salts crystallizing in monoclinic system.

It is very difficult to prepare an oral dosage form such as tablet ordragee from substance having monoclinic crystal structure since theadhesion between the crystal plates is weak and the aggregation ofgranules is difficult to compress.

According to a method well-proved in the practice for tablettingmonoclinic crystalline substances and having weak adhesive properties(e.g. phenylbutazone, phenacetin, barbiturates), the powdered mixturecontaining the active ingredient is pressed after wet granulation [H. A.Lieberman, L. Lachman: Pharmaceutical Dosage Forms, Tablets, Volume 2,Marcel Dkker, Inc., N.Y. (1981)]. In this case, the binding force neededto the tablet formation is provided by the binding agent introducedduring the kneading whereas the optimum compressibility is ensured bythe optimum porosity and flowability developed in the preparingprocedure carried out in a suitable way.

The wet granulation cannot be carried out and the table formation can berealized only by direct compression or briquetting when the activeingredient crystallizes in monoclinic system and is also sensitive tomoisture (e.g. salycilic acid derivatives). In this case the necessaryadhesion is ensured partly by the solid binding agent introduced as apowder mixture and partly by the binding forces developed at theso-called active sites of the granule surfaces [A. S. Rankel et al.: J.Pharm. Soc. 57, 574 (1968)].

In cases of moisture- and light-sensitive substances, the tablets shouldbe provided with a protective coat to prevent any damage during thestorage. A tablet prepared by direct compression should possess anappropriate hardness in order to be useful for a further processing,e.g. dragee formation.

The hardness can be enhanced by increasing the force of compression,however, the density of tablet is increased and the porosity thereof isdecrased by enhancing the force of compression. The disintegration ofthe tablet is decisively influenced by the porosity since the higher thedensity of the tablet is, the slower is the penetration of the aqueousfluid thus, the dissolution of the active ingredient from a tablet ofhigh density is very slow, the desired blood level of the acitveingredient can be achieved only after a long period and thebioavailability of the active ingredient is also low.

During compression a heat effect is developed by the friction of thegranules, whereby the heat-sensitive active ingredients are usuallydecomposed thus, a direct compression or briquetting cannot be employedin these cases.

As a consequence, it is a very difficult task to formulate monocliniccrystalline compounds simultaneously being sensitive to moisture, heatand light effects to tablet composition. No literature reference hasbeen found for the solving of this problem.

The aim of the present invention is to work out a composition, which isuseful for the preparation of a tablet or dragee core from monoclinicmoisture-, heat- and light-sensitive compounds by compression. A furtheraim of the present invention is to prepare a tablet or drageecomposition making possible the rapid absorption of the activeingredient as well as the development of high blood levels after takingthe composition and resulting in a high bioavailability of the activeingredient.

Surprisingly, it has been found that the above aims can be achieved byadding 0.2 to 1.5 parts by weight of an anhydrous alkaline earth metalsalt and 0.5 to 2.5 parts by weight of microcrystalline cellulosecalculated form the active ingredient, to the moisture-, heat- andlight-sensitive active ingredient having monoclinic crystallinestructure.

Thus, the present invention relates to the preparation of a tablet ordragee composition from moisture-, heat- and light-sensitive activeingredient having monoclinic crystalline structure, which compriseshomogenizing the active ingredient with 0.2 to 1.5 parts by weight of ananhydrous alkaline earth metal salt and 0.5 to 2.5 parts by weight ofmicrocrystalline cellulose calculated for the active ingredient as wellas, if desired, with one or more pharmaceutically acceptable carrier(s)and/or additive(s) and compressing the homogeneous mixture thus obtainedto tablets in a manner known per se and, if desired, coating the tabletobtained in a manner known per se.

The invention is based on the recognition that a tablet with suitablebreaking strength can be prepared by using relatively low pressure of150 to 200 MPa, when a tablet is compressed in such a way that a definedamount of an anhydrous alkaline earth metal salt and microcrystallinecellulose are added to the monoclinic moisture-, heat- andlight-sensitive active ingredient. In this case, no increase in the freeenergy occurs at the binding sites, which could induce a chemicalchange, i.e. the decomposition of the active ingredient since thedisplacement at the binding sites of the mobile anions being present inthe crystal structure of the active ingredient is inhibited by thealkaline earth metal salt and simultaneously, a tablet can be obtainedwhich is suitably solid for coating, conveniently disintegrates in thestomach and advantageously releases the active ingredient.

In the process of the invention, e.g. calcium or magnesium hydrogenphosphate, calcium or magnesium dihydrogen phosphate or sulfate orcarbonate may be used as anhydrous alkaline earth metal salts.

Suitable pharmaceutically acceptable carriers in the preparation of theinvention are e.g. talc, maize starch, magnezium stearate, colloidalsilica (Aerosil 200), lactose, glucose, mannitol or the like.

Suitable additives are e.g. one or more binding agent(s), antioxidant(s)disintegrating or flowability-promoting additive(s).

Useful binding agents are e.g. polyvinylpyrrolidone,vinylpirrolidone/vinyl acetate copolymer (Luwiskol VA 64) orpolyethylene glycols.

Useful antioxidants are e.g. ascorbic acid or sodium disulfide.

The active ingredient content of the composition according to theinvention may be varied between broad limits depending from the natureof the active ingredient, type of the disease to be treated, dose of theactive ingredient to be used and the like. The active ingredient contentof the composition is preferably 0.5 to 50% by weight.

The composition according to the invention contains the alkaline earthmetal salt and microcrystalline cellulose in an amount of 2 to 90% byweight, preferably in an amount of 30 to 75% by weight.

The tablets are prepared by homogenizing the ingredients and then bycompressing the homogeneous mixture obtained by using a pressure of 150to 200 MPa in a known manner.

If desired, the tablet may be provided with a coat.

The coat has to satisfy two demands: on the one hand, the activeingredient should be protected against the harmful effect of light andair moisture and on the other hand, a suitable dissolution of the activeingredient has simultaneously to be ensured.

Since the active ingredient is sensitive to moisture, no aqueous systemcan be used and an organic solvent can only by considered for coating.

The coat conveniently contains a hydrophilic component (such aspolyethylene glycol, water-soluble cellulose ethers orvinylpirrolidone/vinyl acetate copolymer) and a hydrophobic component(ethylcellulose or acrylate/metacrylate ester copolymer). The weightratio of hydrophilic components to the hydrophobic components ispreferably 1:1 to 1:1.5.

Pharmaceutically acceptable organic solvents being capable to dissolvethe components of the coat, such as alcohols and ketones, e.g. ethanol,isopropanol, acetone or their mixtures may be used as solvents forcoating material.

The mixture containing ethanol/acetone or isopropanol/acetone in avolume ratio of 1:0.2 to 1:1.5 is preferred as solvent.

The coating process is carried out by using a suspension prepared withan organic solvent containing the hydrophilic and hydrophobic substancesand optionally other additives (e.g. light-protective dyes such as aniron oxide pigment) in a known manner.

The process according to the invention is particularly useful forpreparing an antiarrhythmic active pharmaceutical compositioncomposition containing as active ingredient an aminoguanidine derivativeof the general formula (I), wherein

R¹, R² and R³ stand independently from each other, for hydrogen, halogenor C₁₋₄ alkyl, nitro C₁₋₄ alkoxy or trifluormethyl group;

R⁴ and R⁵ represent independently from each other, a C₁₋₄ alkyl group;

R⁶ and R⁷ represent, independently from each other, hydrogen or C₁₋₄alkyl or C₂₋₄ alkenyl group or their acid addition salts crystallizingin monoclinic system.

The aminoguanidine derivatives of general formula (I) and their acidaddition salts are moisture-, light-and heat-sensitive and aretransformed to vivid red-coloured phenylazoformamidine derivatives by anauto-oxidation reaction.

When the hydrochloride of1-(2,6-dimethylphenyl)-4,4'-dimethylaminoguanidine being within thescope of the general formula (I) is subjected to a wet granulationaccording to known processes and then compressed to tablets (shown inExample 1), then the active ingredient of the compsition significantlydecomposes within a short time interval (e.g. 10 days). The samedecomposition of the active ingredient has not been observed oncompositions prepared according to the invention: the compositionremained stable during a longer time of storage and even in the case ofa higher moisture content.

Based on clinical investigations, on using1-(2,6-dimethylphenyl)-4,4'-dimethylaminoguanidine hydrochloride beingwithin the scope of the general formula (I) as active ingredient of thecomposition according to the invention, the half life measured in theblood increased from 2.4 hours to 3.2 hours in comparison to aninjectable composition containing the same active ingredient, whereasthe relative bioavailability of the active ingredient proved to be about80%.

The process according to the invention is illustrated in detail by thefollowing non limiting Examples.

1-(2,6-Dimethylphenyl)-4,4'-dimethylaminoguanidine hydrochloride wasused as active ingredient in all these Examples. The amounts given inthe Examples mean parts by weight (pbw) in each case when it is notnoted otherwise.

COMPARATIVE EXAMPLE 1

    ______________________________________                                        Ingredients        Amounts                                                    ______________________________________                                        Active ingredient  500                                                        Lactose            1005                                                       Maize starch       900                                                        Microcrystalline cellulose                                                                       420                                                        Polyvinylpyrrolidone                                                                             85                                                         Ascorbic acid      30                                                         Magnesium stearite 20                                                         Talc               40                                                         ______________________________________                                    

The active ingredient was admixed with maize starch, microcrystallinecellulose and lactose. Polyvinylpyrrolidone and ascorbic acid weredissolved in 800 ml of ethanol and the homogeneous mixture wasgranulated with the latter solution. After drying, the granulate washomogenized with the substances of the outer phase and then compressedto flat edge tablets weighing 300 mg each by using a compressionpressure of 100 to 150 MPa. The breaking strength of the tablets was 50to 75N.

The tablets obtained were subjected to storage experiments carried outin the presence of moisture and heat as well as light load. According toour observations the colour of the tablet became deeper and adecomposition product of 1 to 2% by weight could be detected at atemperature of 60° C. or at room temperature in the presence of arelative moisture content of 80% during 10 days. This decompositionprocess could not be prevented by ascorbic acid.

EXAMPLE 2

    ______________________________________                                        Ingredients        Amounts                                                    ______________________________________                                        Active ingredient  500                                                        Lactose            810                                                        Maize starch       900                                                        Colloidal silicon dioxide                                                                        15                                                         Polyvinylpyrrolidone                                                                             85                                                         Microcrystalline cellulose                                                                       600                                                        Ascorbic acid      30                                                         Talc               40                                                         Magnesium stearate 20                                                         ______________________________________                                    

The sieved components with the prescribed particle size were carefullyhomogenized and the aggregation of granules obtained was compressed tobiconvex tablets of 10 mm in diameter weighing 300 mg each by using acompression pressure of 150 MPa on a rotating tablet machine.

The tablets possess a breaking strength of 40 to 50N.

EXAMPLE 3

    ______________________________________                                        Ingredients            Amounts                                                ______________________________________                                        Active ingredient      1000                                                   Maize starch           660                                                    Anhydrous calcium hydrogen phosphate                                                                 900                                                    Microcrystalline cellulose                                                                           1540                                                   Vinylpyrrolidone/vinyl 160                                                    acetate copolymer                                                             Talc                   120                                                    Ascorbic acid           60                                                    Magnesium stearate      40                                                    Colloidal silica        20                                                    ______________________________________                                    

The sieved components with the prescribed particle size were carefullyhomogenized and the aggregation of granules obtained was compressed tobiconvex tablets of 9 mm in diameter weighing 300 mg each by using acompression pressure of 150 MPa on a rotating tablet machine.

The tablets possess a breaking strength of 50 to 80 N.

The dragee scores obtained as described above were coated with asuspension containing the ingredients listed below in a pan suitable forfilm coat formation.

    ______________________________________                                        Ingredients         g                                                         ______________________________________                                        Ethylcellulose      56                                                        Vinylpyrrolidone/vinyl                                                                            56                                                        acetate copolymer                                                             Talc                68                                                        Magnesium stearate  10                                                        Titanium dioxide     4                                                        Yellow iron oxide pigment                                                                          6                                                        Ethanol             1080                                                      Acetone             1000                                                      ______________________________________                                    

The tablet prepared as described above was stored in a relative moisturecontent of 75% and 95%, respectively for 12 months. The results areshown in Table I.

                  TABLE I                                                         ______________________________________                                        Relative moisture content                                                     75%                 95%                                                       Months mg/tablet decomp. %  mg/tablet                                                                             decomp. %                                 ______________________________________                                        0      49.85     0          0       0                                         1      49.82     0.09       50.17   0.2                                       2      49.22     0.10       49.82   0.1                                       4      49.73     0.90       49.37   1.7                                       12     49.98     0.05       --      --                                        ______________________________________                                    

In order to determine the heat-stability, the tablets were stored at24°, 40°, 50° or 60° C., respectively for 12 months. The results areshown in Table II.

                  TABLE II                                                        ______________________________________                                        Temperature                                                                   Time of 24° C.                                                                           40° C.                                                                           50° C.                                                                         60° C.                             storage mg/    dec.   mg/  dec. mg/  dec. mg/  dec.                           months  tab.   %      tab. %    tab. %    tab. %                              ______________________________________                                        0       --     --     --   --   --   --   --   --                             1       --     --     --   --   49.06                                                                              0.25 49.04                                                                              0.09                           2       --     --     48.88                                                                              0.13 48.35                                                                              0.13 48.23                                                                              0.13                           4       --     --     48.06                                                                              0.40 48.00                                                                              0.60 47.32                                                                              0.13                           8       52.32  0.35   49.10                                                                              --   --   --   --   --                             12      51.06  0.45   --   --   --   --   --   --                             ______________________________________                                    

The absorption of the active ingredient from the tablet prepared asdescribed above was investigated in dogs. The composition showed anabsorption coefficient (k_(a)) of 0.9 to 1.6 h⁻¹ and an eliminationcoefficient (k_(e)) of 0.20 to 0.25 h⁻¹, i.e. the values indicate arapid absorption.

The preceding results were supported by pharmacokinetic examinationscarried out in the human I phase clinical trials. A value of 1.4 h⁻¹ wasobtained for the absorption coefficient (k_(a)) in the human trials. Therelative bioavailabilty calculated from the AUC values proved to be 80%.This value can be considered to be very high as a part of theantiarrhytmic reference drugs (e.g. aminodarone) were not absorbed and abioavailability of 40 to 70% has only been achieved in case of otherdrugs (e.g. quinidine, lidocaine) [P. G. Welling et al.:Pharmacokinetics of Cardiovascular, Central Nervous System andAntimicrobial Drugs, London, (1985)].

EXAMPLE 4

    ______________________________________                                        Ingredients            Amounts                                                ______________________________________                                        Active ingredient      1000                                                   Maize starch           600                                                    Anhydrous calcium hydrogen phosphate                                                                 900                                                    Microcrystalline cellulose                                                                           1800                                                   Vinylpyrrolidone/vinyl acetate                                                                       160                                                    copolymer                                                                     Talc                   120                                                    Ascorbic acid           60                                                    Magnesium stearate      40                                                    Colloidal silica        20                                                    ______________________________________                                    

After crushing and sieving to the desired particle size, the componentswere carefully homogenzied, then the aggregation of granules obtainedwas compressed to biconvex tablets of 11 mm in diameter weighing 430 geach by using a compression pressure of 200 MPa on a rotating tabletmachine.

The tablets possess a breaking strength of 80 to 100N. The dragee scoreswere uniformly coated in an automated dragee-forming apparatus with asuspension containing the following ingredients.

    ______________________________________                                        Ingredients             g                                                     ______________________________________                                        Acrylic acid/metacrylic acid copolymer                                                                60                                                    Polyethylene glycol 600 40                                                    Talc                    80                                                    Magnesium stearate      10                                                    Titanium dioxide         4                                                    Yellow iron oxide pigment                                                                              6                                                    Isopropanol             1000                                                  Acetone                 900                                                   ______________________________________                                    

EXAMPLE 5

    ______________________________________                                        Ingredients          Amount                                                   ______________________________________                                        Active ingredient    2000                                                     Maize starch         110                                                      Anhydrous calcium hydrogen                                                                         450                                                      phosphate                                                                     Microcrystalline cellulose                                                                         1200                                                     Polyvinylpyrrolidone 200                                                      Talc                 120                                                      Sodium disulfite      50                                                      Magnesium stearate    40                                                      Colloidal silica      30                                                      ______________________________________                                    

The sieved components with the prescribed particle size are carefullyhomogenzied, then the aggregation of granules obtained is compressed tobiconvex tablets of 11 mm in diameter weighing 420 mg each by using acompression pressure of 150 MPa on a rotating tablet machine.

The tablets possess a breaking strength of 90 to 100N.

The tablet scores are uniformly coated in an automated dragee-formingapparatus with a suspension containing the following ingredients:

    ______________________________________                                        Ingredients        g                                                          ______________________________________                                        Ethylcellulose     58                                                         Hydroxypropylcellulose                                                                           50                                                         Talc               70                                                         Magnesium stearate 11                                                         Titanium dioxide    3                                                         Red iron oxide pigment                                                                            8                                                         Ethanol            1800                                                       Acetone            400                                                        ______________________________________                                    

What is claimed is:
 1. A process for the preparation of a tablet ordragee composition containing a moisture-, heat- and light-sensitiveaminoguanidine derivative of formula (I), having a monocliniccrystalline structure, ##STR2## wherein R¹, R² and R³ standindependently from each other, for hydrogen, halogen or C₁₋₄ alkyl,nitro, C₁₋₄ alkoxy or trifluoromethyl group,R⁴ and R⁵ representindependently from each other, a C₁₋₄ alkyl group; R⁶ and R⁷ represent,independently from each other, hydrogen, C₁₋₄ alkyl or C₂₋₄ alkenylgroup; or a pharmaceutically acceptable acid addition salt thereof; theprocess comprising the steps of:homogenizing the formula (I)aminoguanadine derivative with 0.2 to 1.5 parts by weight of ananhydrous alkaline earth metal salt selected from the group consistingof a hydrogen phosphate salt, a dihydrogen phosphate salt, a hydrogencarbonate salt, a carbonate salt and a sulfate salt of calcium andmagnesium, 0.5 to 2.5 parts by weight of microcrystalline cellulose,0.05 to 0.3 parts by weight of a binding material selected from thegroup consisting of polyvinylpyrrolidone and vinylpyrrolidone/vinylacetate copolymer, 0.01 to 0.04 parts by weight of a glidant which iscolloidal silicone dioxide, and 0.01 to 0.1 parts by weight of anantioxidant selected from the group consisting of ascorbic acid andsodium disulfide calculated for the active ingredient, and one or morepharmaceutically acceptable anti-adhesive, lubricating and fillingadditive(s); compressing the homogeneous mixture obtained to tablets;and coating the tablets thus obtained.
 2. A process as claimed in claim1, wherein the active ingredient is1-(2,6-dimethylphenyl)-4,4'-dimethylaminoguanidine hydrochloride.
 3. Aprocess as claimed in claim 1, which comprises:homogenizing as theactive ingredient 1-(2,6-dimethylphenyl)-4,4'-dimethyl aminoguanidinehydrochloride with 0.2 to 1.5 parts by weight of anhydrous calciumhydrogen phosphate and 0.5 to 2.5 parts by weight of microcrystallinecellulose calculated for the active ingredient.
 4. A process as claimedin claim 1, wherein the active ingredient is present in an amount of 0.5to 50% by weight in the tablet or dragee composition prepared.
 5. Aprocess as claimed in claim 1, wherein the anhydrous alkali earth metalsalt and the microcrystalline cellulose are present in an amount of 2 to90% by weight in the tablet or dragee composition prepared.